Alzheimer's Disease (AD), the most common form of dementia, is characterized by two pathological hallmarks: tau neurofibrillary tangles (NFT) and amyloid- (A) plaques. As an alternative approach to current A-targeted therapies, we propose to focus on tau. Several groups have shown that mice lacking endogenous tau, when crossed to A depositing hAPP mice, show a significant increase in learning/memory performance and are protected from chemically induced seizures. Our preliminary data show that, as predicted from the tau knockout, lowering total tau protects against seizures. Surprisingly, we also have found that converting the 4R tau isoform to 3R tau without changing total tau also protects against seizures. We now propose to determine whether converting 4R tau to 3R will protect against amyloid beta induced cognitive deficits in PSAPP mice. In addition, using measures of neuronal excitability in response to GABA antagonists, we will correlated the amount of tau knockdown and shift from 4R to 3R with the change in neuronal excitability. Using immunohistochemical and biochemistry, we test whether changing tau isoforms changes tau localization or the components of the synapse. The antisense oligonucleotide approach used in this grant to modify tau has been used successfully in a Phase I clinical trial for patients with ALS. Thus, demonstrating a therapeutic benefit using oligos that change 4R to 3R in mice may be readily translatable to human.